Tuberculosis (TB) in incarcerated populations is a serious problem, due to the large proportion of inmates who are at high risk of having latent tuberculosis infection (LTBI) and developing active disease. Completion of treatment of LTBI has not been successful in jails, mainly because inmates are frequently released before finishing a 6-9 month course of standard therapy with daily isoniazid (INH), and because they have low rates of completing therapy in the community. Effective treatment of LTBI is complicated by length of therapy and toxicity of the drugs used against LTBI. Short-course therapies for LTBI may address this problem but they have not been studied adequately to answer questions about side effects, completion rates, and overall cost. We propose a two arm, open label randomized trial to test the effects of a short-course therapy for LTBI in jailed inmates; rifampin given daily for 4 months as compared to INH given twice weekly for 9 months. A sample of 972 consented and enrolled participants will be administered directly observed therapy (DOT) in jail. The study protocol includes links to the TB Clinic for post-release DOT, and close clinical and laboratory monitoring throughout the course of therapy. Participants will be followed, in jail and after release, for one year after enrollment, to measure three outcomes: toxicity, adherence, and cost-effectiveness. Toxicity leading to stopping drug will be analyzed by study group, and other predictors will be examined, such as age, alcohol use and hepatitis B and C. Adherence, measured by completion of therapy, will be compared by study group, and other predictors will be examined, including sociodemographic variables, intent to adhere, and stability of housing. Cost-effectiveness will be compared by study group and will be calculated using direct costs of administering and monitoring care and costs of re-starting care in this population with a high rate of re-arrest, measured against the cost of prevented cases of TB. Short course regimens are promising in the inmate population to treat LTBI and eliminate risk of progression to active disease. This study will answer questions about the safety of rifampin compared directly to INH. Analysis of completion of therapy and cost-effectiveness of this regimen will provide important information for policy change in the way LTBI is managed in jail.